Procyanidin B3 Prevents Articular Cartilage Degeneration and Heterotopic Cartilage Formation in a Mouse Surgical Osteoarthritis Model

Abstract

Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H2O2-induced apoptosis in primary chondrocytes, suppressed H2O2- or IL-1ß−induced nitric oxide synthase (iNOS) production, and prevented IL-1ß−induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification.

Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

“…While previous studies showed that procyanidins exert a chondroprotective effect in part by suppressing oxidative stress-induced factors [29,30,32], we revealed that procyanidins inhibit VEGF-induced signaling in the articular cartilage of DMM-induced OA mice. VEGF signaling plays a significant role in OA progression, including enhancing expression of pro-inflammatory cytokines and catabolic mediators in chondrocytes [54,70].…”

“…In animal studies, grape seed extract, rich with procyanidins, reduce ROS activity and expression of matrix metalloproteinases (MMPs) in the articular cartilage of monosodium iodoacetate-induced OA rats [30], and procyanidins extracted from grape seeds ameliorate collagen-induced arthritis (CIA) in mice through regulation of the toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway [31]. Notably, daily oral administration of procyanidin B3, one of the components of procyanidins, was shown to mitigate OA pathogenesis in mice subject to medial collateral ligament transection and medial meniscectomy by, at least in part, suppressing induced nitric oxide synthase (iNOS) [32]. However, whether procyanidins, procyanidin B2 and procyanidin B3, or other components of procyanidins exert chondroprotective effects via other OA-relevant pathways is unknown.…”

Ascorbic acid provides protection for human chondrocytes against oxidative stress

“…An augmented differentiation index is indicative of the active maintenance of the hyaline phenotype of chondrocytes (36,37). By contrast, an upregulated expression of Col1a1 or a decline in the differentiation index represented the formation of fibrocartilage rather than hyaline cartilage (37,38). The present study revealed that (Figs.…”

Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis

“…We demonstrated that in the murine meniscectomy model of OA, calcium-containing crystal deposits were formed in the articular space prior to cartilage degradation (see online supplementary figure S1). These crystal deposits were previously identified as hypertrophic calcification,36 ectopic bone,37 mineralised area38 and heterotopic cartilage,39 but their chemical characterisation and their role in OA had never been determined. Starting from 1 month after OA induction, microCT-scan revealed multiple deposits within the joint, detached from bone, so that they could not be considered as osteophytes.…”